Glucose dependent insulinotropic polypeptide analogs, pharmaceutical compositions and use thereof

Patent metadata

Field	Value
Publication number	US-9453062-B2
Application number	US-201214125061-A
Country	US
Kind code	B2
Filing date	Jun 8, 2012
Priority date	Jun 10, 2011
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

The present invention provides a GIP analog, which is derived from GIP (1-29, SEQ ID NO: 1), has both GLP-1 agonist activity and GIPR stimulation activity, and comprises an amino acid sequence represented by the following formula I: Tyr-A2-A3-Gly-Thr-Phe-A7-Ser-Asp-Tyr-Ser-A12-A13-A14-A15-Lys-A17-A18-A19-A20-A21-A22-A23-A24-Trp-Leu- A27-A28-A29-Y. The present invention also provides a pharmaceutical composition comprising the GIP analog and use thereof.

First claim

We claim:

1. A glucose-dependent insulinotropic polypeptide (GIP) analog derived from GIP (1-29, SEQ ID NO: 1), wherein the GIP analog has both GLP-1 agonist activity and GIPR stimulation activity, is amidated at the C-terminus thereof, and comprises an amino acid sequence represented by the following formula I:
Tyr-A2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-A13-Met-Glu-Lys-A17-A18-A19-A20-A21-A22-A23-A24-Trp-Leu-A27-A28-A29-Y  (SEQ ID NO: 109)

wherein
A2 is selected from the group consisting of Gly, Aib, and d-Ala;
A13 is selected from the group consisting of an amino acid residue having aryl group and is selected from Tyr, Phe(4-F), Phe(4-NO 2 ), and Phe(4-NH 2 );
A17 is selected from the group consisting of Ile, Glu, and Gln;
A18 is selected from the group consisting of Ala and His;
A19 is selected from the group consisting of Val, Ala, Leu, Gln and Ile;
A20 is selected from the group consisting of Arg, Lys-Z, Gln, Glu, Asp and Cys-Z;
A21 is selected from the group consisting of Glu, Asp and Leu;
A22 is selected from the group consisting of Phe, Phe(4-F), and Phe(4-Cl);
A23 is selected from the group consisting of Ile and Val;
A24 is selected from the group consisting of Ala, Glu, Lys-Z and Cys-Z;
A27 is selected from the group consisting of Val, Leu, Ala, and Lys-Z;
A28 is selected from the group consisting of Lys-Z, Ala, Arg, and Asn;
A29 is selected from the group consisting of Gly, Gln and Arg;
Y is selected from the group consisting of: A30 and -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40 (SEQ ID NO. 104), or absent;
A30 and A40 are independently selected from the group consisting of -(Lys) n -Z and -Cys-Z, or absent;
Z is selected from the group consisting of -(Glu) m -PEG, -(Glu) m -biotin and -(Glu) m -fatty acid, or absent;
n is an integer selected from 1 to 6;
m is an integer selected from 0 to 3;
wherein, a lactam linkage is optionally formed between the amino acids at positions i and i+4 of the GIP analog; i is an integer selected from 12 to 24;
or a pharmaceutically acceptable salt thereof,
wherein the GLP-1 agonist activity is more dominant than the GIPR stimulation activity.

2. The GIP analog according to claim 1 , wherein in formula I:
A13 is selected from the group consisting of an amino acid residue having aryl group and is selected from Tyr, Phe(4-F), Phe(4-NO 2 ), and Phe(4-NH 2 )
A18 is Ala;
A19 is selected from the group consisting of Val and Ala;
A20 is selected from the group consisting of Arg, Lys-Z, Glu, Asp and Cys-Z;
A21 is selected from the group consisting of Glu and Leu;
A22 is Phe;
A23 is Ile;
A27 is selected from the group consisting of Val and Lys-Z;
A28 is selected from the group consisting of Lys-Z and Asn; and
A29 is Gly;
Z is selected from the group consisting of -(Glu) m -PEG, -(Glu) m -biotin and -(Glu) m -fatty acid, or absent;
m is an integer selected from 0 to 3.

3. The GIP analog according to claim 1 , wherein in formula I,
Y is A30 or absent;
A30 is selected from the group consisting of -(Lys) n -Z and -Cys-Z, or absent;
Z is selected from the group consisting of -(Glu) m -PEG, -(Glu) m -biotin and -(Glu) m -fatty acid, or absent;
n is an integer selected from 1 to 6;
m is an integer selected from 0 to 3.

4. The GIP analog according to claim 1 , wherein in formula I,
Y is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40  (SEQ ID NO: 104);

A40 is selected from the group consisting of -(Lys) n -Z and -Cys-Z, or absent;
Z is selected from the group consisting of -(Glu) m -PEG, -(Glu) m -biotin and -(Glu) m -fatty acid, or absent;
n is an integer selected from 1 to 6;
m is an integer selected from 0 to 3.

5. The GIP analog according to claim 1 , wherein in formula I: Y is absent.

6. The GIP analog according to claim 1 , wherein in formula I: Y is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 107).

7. The GIP analog according to claim 1 , wherein formula I comprises one or more amino acids selected from the group consisting of: Aib at position A2; Tyr at position A13; Glu at position A17; Val at position A19; and Arg at position A20.

8. The GIP analog according to claim 1 , wherein in formula I:
A24 is Cys-Z;
Z is -(Glu) m -PEG;
m is an integer selected from 0 to 3.

9. The GIP analog according to claim 1 , wherein in formula I:
A30 and A40 are independently (Lys) n -Z;
Z is selected from the group consisting of -(Glu) m -PEG, -(Glu) m -biotin and -(Glu) m -fatty acid, or absent;
n is an integer selected from 1 to 6;
m is an integer selected from 0 to 3.

10. The GIP analog according to claim 1 , wherein in formula I:
Z is selected from the group consisting of -(Glu) m -PEG and -(Glu) m -fatty acid; and
m is an integer selected from 0 to 2.

11. The GIP analog according to claim 1 , wherein in formula I, a lactam linkage is formed between the amino acids at positions i and i+4 of the GIP analog; i is an integer selected from 12, 16 and 24.

12. The GIP analog according to claim 1 , wherein the fatty acid is selected from the group consisting of myristic acid, palmitic acid, stearic acid and cholic acid.

13. The GIP analog according to claim 1 , wherein the molecular weight of PEG is from 5 kDa to 40 kDa.

14. The GIP analog according to claim 1 , wherein the GIP analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 65, 18 to 21, 24 to 35, 38 to 47, 49 to 59, 62 to 64, 66 to 74, 76 to 78 and 80 to 83; or a pharmaceutically acceptable salt thereof.

15. The GIP analog according to claim 1 , wherein the GIP analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 65, 63, 80, 52, 18, 35, 74, 19, 20, 21, 45, and 72; or a pharmaceutically acceptable salt thereof.

16. The GIP analog according to claim 1 , wherein the GIP analog comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO: 52, wherein at least one fatty acid moiety is linked at position 20, 24 and/or the C-terminal;
SEQ ID NO: 74, wherein at least one fatty acid moiety is linked at position 20, 24 and/or the C-terminal;
SEQ ID NO: 72 wherein at least one fatty acid moiety is linked at position 20, 24 and/or the C-terminal;
SEQ ID NO: 98, wherein at least one PEG moiety is linked at position 20, 24 and/or the C-terminal;
SEQ ID NO: 74, wherein at least one PEG moiety is linked at position 20, 24 and/or the C-terminal;
SEQ ID NO: 65, wherein at least one PEG moiety is linked at position 20, 24 and/or the C-terminal;
SEQ ID NO: 74 with PEG moiety linked at position 24 and a fatty acid moiety linked at the C-terminal; and
pharmaceutically acceptable salts thereof.

17. The GIP analog according to claim 10 , wherein Glu is gamma-Glu.

18. The GIP analog according to claim 1 , wherein the molecular weight of PEG is 20 kDa, 30 kDa, or 40 kDa.

19. A pharmaceutical composition comprising an effective amount of a GIP analog according to claim 1 , a pharmaceutically acceptable diluent, carrier or excipient, and an optional anti-diabetes agent selected from the group consisting of insulins, biguanides, sulfonylurea, rosiglitazone, pioglitazone, alpha-glucosaccharase inhibitors, and aminodipeptidase IV inhibitors.

20. The pharmaceutical composition according to claim 19 , wherein the pharmaceutical composition is in the form of an injectable formulation or lyophilized powder.

21. A method for treating metabolic disorders, comprising administering an effective amount of the GIP analog or the pharmaceutically acceptable

Assignees

• Ma Tao
• Xu Shusen
• Liu Zhijun
• Zhang Bo
• Shen Ning
• Yang Hai
• Zhang Wei
• Li Yuhua
• Moon Sunghwan
• Kim Maengsup
• Beijing Hanmi Pharmaceutical Co Ltd

Inventors

• Ma Tao
• Xu Shusen
• Liu Zhijun
• Zhang Bo
• Shen Ning
• Yang Hai
• Zhang Wei
• Li Yuhua
• Moon Sunghwan
• Kim Maengsup

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/12

  Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10) · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title